Atherosclerosis is a chronic inflammatory disease associated with the activation of both innate and adaptive immune responses. Minority populations and young women with systemic lupus erythematosus are particularly prone to the development of atherosclerosis. Recently, a unique group of T lymphocytes, called invariant natural killer T (iNKT) cells, have been implicated in atherogenesis and lupus. This Project will test the hypothesis that iNKT cells are chronically activated during hyperlipidemia and that this conversion is uniquely involved in regulating and/or modulating an inflammatory response that exacerbates atherosclerosis and dysregulates immunity. This hypothesis is based on key preliminary studies demonstrating that (a) iNKT cell numbers and functions are altered in spontaneously hyperlipidemic apoE-deficient (apoE-/-) mice;(b) iNKT cells of apoE-/- mice express phenotypic markers distinct from wild type iNKT cells, suggesting activation;(c) absence of iNKT cells in apoE-/- mice reduces atherosclerosis but aggravates lupus;and (d) specific activation of iNKT cells in vivo is proatherogenic but protects against lupus. Based on these findings, the overall objective of this Project is to characterize the immunoregulatory mechanism(s) by which iNKT cells promote lesion formation in the artery wall. Our specific aims are to: (1) investigate the effects of hyperlipidemia and atherosclerosis on iNKT cell numbers and functions in apoE-/- mice;(2) investigate the role of cytokine production by iNKT cells and subsequent immune activation in atherosclerosis and (3) determine the role of iNKT cells in lupus-accelerated atherosclerosis. Relevance to Public Health: Coronary heart disease associated with atherosclerosis is the primary cause of mortality in the United States. At extremely high risk for suffering a fatal cardiac event are young women with lupus. Lupus-accelerated atherosclerosis is independent of cholesterol levels and is thought to be largely associated with autoimmune dysregulation. iNKT cells represent some of the most potent immune regulators. Therefore, understanding their significance in lupus and atherosclerosis will provide valuable insights for the future generation of immunotherapy to treat both lupus and heart disease.